Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor, is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca.sup.2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Stuerzebecher et al, Thrombosis Research 1976, 9, 637-646, report comparative studies of a number of benzamidine derivatives as factor Xa inhibitors. The most active inhibitors were 3-amidino-phenylaryl derivatives. In Thrombosis Research 1980, 17, 545-548, Stuerzebecher et al detail factor Xa inhibitory activity of a series of a,a'-bis-(4-amidinobenzyl)cycloalkanones, a,a'-bis-(4-aminobenzylidene)- and a,a'-bis-(3-aminobenzylidene) cycloalkanones with 5 to 8-membered rings, the corresponding non-cyclic derivatives, and derivatives containing only one amidino group.
Tidwell et al, Thrombosis Research 1980, 19, 339-349, describe factor Xa inhibitory activity of a series of aromatic mono- and di-amidines. The amidino aromatic moieties are either bicyclic heterocycles or amidino-phenoxy groups.
Hauptmann et al, Blood Coagulation and Fibrinolysis 1993, 4, 577-582, and Thromb. Haemostasis 1990, 63(2), 220-223, address testing of several synthetic compounds as factor Xa inhibitors: Na-tosylglycyl-3-amidinophenylalanine methyl ester; 2,7-bis(4-amidinobenzylidene)-cycloheptanone-(1); Na-tosyl-4-amidinophenylalanine piperidide; Na-naphthylsulphonylglycyl-4-amidinophenylalanine piperidide; 4-methyl-1-N.sup.2 -(methyl-1,2,3,4-tethydro-8-quinolinesulphonyl-L-arginyl-2-piperidine carbonic acid; and D-phenylalanyl-L-propyl-L-arginine chloromethyl ketone.
Nagahara et al, EP 0,540,051 A1 and J. Med. Chem. 1994, 37, 1200-1207 and Hara et al, Thromb. Haemostas 1994, 71(3), 314-319, discuss amidino aromatic bicycles which have factor Xa inhibitory activity. Examples include amidino naphthylenes, amidino-indoles, amidino-benzimidazoles, and amidino-benzothiophenes. Amidino phenyl derivatives are not addressed. JP 05078344, another publication in the above-noted family, describes symmetrical factor Xa inhibitors containing terminal amidino aromatic bicycles.
Bovy et al, WO 93/08164, report substituted heterocyclic derivatives of the formula: ##STR2## which are useful as platelet aggregation modulators or inhibitors. No mention is made of using the above compounds as factor Xa inhibitors.
Himmelsbach et al in CA 2,054,850 discuss aggregation inhibiting compounds of the formula: EQU B--X--A--Y--E
wherein A may be a cyclic imino such as pyrrolidine and amidst the various definitions of B and X one can find groups such as amidino and arylene. The combination of A--Y--E, however, is not considered to be useful for the present invention. Thus, the compounds of Himmelsbach et al differ from those of the present invention. Moreover, inhibition of factor Xa is not discussed in Himmelsbach et al as a use for the compounds of the above formula.
Despite the foregoing, more efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. Thus, it is desirable to discover new factor Xa inhibitors.